The structure and biogenesis of cell membranes in normal and cancer cells will be studied using the techniques of somatic cell genetics. Differences will be studied in order to evaluate the genetic and epigenetic basis for malignancy and to evaluate possibilities of exploiting these differences in the design of cancer chemotherapy. We will use diphtheria toxin, abrin, ricin and other lectins for the isolation of membrane mutants. Toxin and lectin binding sites will be characterized with regard to 1) structure, 2) biogenesis, 3) density, 4) mobility and 5) internalization and turnover. Mutant cell lines resistant to these toxins or lectins will be derived, and the phenotypes responsible for resistance studied. Genetic complementation by intraspecific cell hybridization will be performed to classify the types of genetic alterations involved. Interspecific cell hybrids between toxin or lectin resistant mouse cells and normal human cells will be constructed and used to assign the genes responsible for particular phenotypes to specific human chromosomes. Diphtheria toxin, abrin and ricin consist of two subunits. One subunit is responsible for binding to cell receptors; the other for cytotoxic activity. We will evaluate the in vitro cytotoxity towards normal and cancer cells of the 1) intact toxins, 2) toxin subunits, 3) intact toxins conjugated to antibodies and 4) toxin subunits conjugated to antibodies. As a model system we will evaluate the effectiveness and specificity of toxin conjugated with antibody specific for human beta2-microglobulin, a human cell surface protein. This system provides an in vitro model for possible chemotherapeutic use of toxins conjugated with antibodies directed against tumor-specific antigens.